This invention is concerned with a process for preparing 17.beta. substituted 3-oxo-4 azasteroids by utilizing an imidazolide as a common intermediate from which these azasteroids may be formed.
Heretofore 17.beta. substituted 3-oxo-4 azasteroids have been produced by using different synthetic processes for each azasteroid.
European Patent Application 85301122.9 discusses the synthesis of 17 substituted 3-oxo-4-azasteroids. This process consists of the formation of a 17.beta. (2-pyridylthiocarbonyl)3-oxo-4-azasteroid which can be substituted at the four position and can have a double bond at the 1,2 positions. This compound is then reacted with a substituted amine to form the corresponding 17.beta. (N-carbamoyl)3-oxo-4-azasteroid, or it can be reacted with a Grignard reagent to form a 17.beta. acyl-3-oxo-4-azasteroid. While this process is feasible, it has the disadvantage of requiring chromatography to obtain the final product.
Rasmusson et. al., J. Med. Chem. 1986, 29, 2298-2315 also discusses the synthesis of 17.beta. 3-oxo-4-azasteroids by reacting a 17.beta. carboxy-androstan-3-one with an acid chloride, which activates the 17.beta. carboxy functionality and forms the corresponding 17.beta. carboxychloro compound, followed by treatment with an amine to form the 17.beta. amido analog. This product is then treated with an oxidizing agent and an amine to introduce a nitrogen into the A ring of the steroid to form the 17.beta. substituted-3-oxo-4-azasteroid. The disadvantage of this process is that the nitrogen cannot be introduced into the A ring of the steroid until after the amination of the 17.beta. carboxychloro since the lactam ring formed would interfere with the acid chloride activation. See also U.S. Pat. Nos. 4,220,775 and 4,377,584 which discuss the synthesis of 17.beta. substituted 3-oxo-4-azasteroids.
The 17.beta. substituted 3-oxo-4-azasteroids formed by the process of the present invention may also contain a double bond between the 1,2 positions of the A ring of the azasteroid. This double bond can be introduced into the azasteroid at any point during the process of the present invention. This includes prior to the formation of the imidazolide, after the imidazolide formation, or after the introduction of the 17.beta. ketone or amide. The 1,2 double bond introduction is well known in the art. See Back, T. G., J. Org. Chem. 46: 1442 (1981); and Rasmussen et. al., J. Med. Chem. 29, 2298 (1986).
The imidazolide formation, which is part of the present invention, is necessary in order to activate the 17.beta. carboxylic acid functionality of the 3-oxo-4-azasteroid. The formation of an imidazolide and its use as an intermediate to form other compounds is known in the art. See Brooks et. al., Angew. Chem. Int. Ed. Engl., 18 (1979) No. 1. Brooks et. al. discusses the use of an imidazolide intermediate in ketone formation. However, there is no discussion of the use of an imidazolide intermediate in the formation of an amide, such as is disclosed in the present invention. Also, it has not been known heretofore to utilize an imidazolide intermediate in the synthesis of 3-oxo-4-azasteroids.
The process of the present invention provides for the synthesis of an imidazolide which is used as a common intermediate from which various 17.beta. substituted 3-oxo-4-azasteroids may be formed. This avoids the multistep procedures and the use of chromatography associated with the prior art.